Engineering of extracellular vesicles for efficient intracellular delivery of multimodal therapeutics including genome editors

Xiuming Liang (), Dhanu Gupta, Junhua Xie, Elien Wonterghem, Lien Hoecke, Justin Hean, Zheyu Niu, Marziyeh Ghaeidamini, Oscar P. B. Wiklander, Wenyi Zheng, Rim Jawad Wiklander, Rui He, Doste R. Mamand, Jeremy Bost, Guannan Zhou, Houze Zhou, Samantha Roudi, H. Yesid Estupiñán, Julia Rädler, Antje M. Zickler, André Görgens, Vicky W. Q. Hou, Radka Slovak, Daniel W. Hagey, Olivier G. Jong, Aileen Geobee Uy, Yuanyuan Zong, Imre Mäger, Carla Martin Perez, Thomas C. Roberts, Dave Carter, Pieter Vader, Elin K. Esbjörner, Antonin Fougerolles, Matthew J. A. Wood, Roosmarijn E. Vandenbroucke, Joel Z. Nordin () and Samir EL Andaloussi ()
Additional contact information
Xiuming Liang: Karolinska Institutet
Dhanu Gupta: Karolinska Institutet
Junhua Xie: VIB
Elien Wonterghem: VIB
Lien Hoecke: VIB
Justin Hean: Evox Therapeutics Limited
Zheyu Niu: Karolinska Institutet
Marziyeh Ghaeidamini: Chalmers University of Technology
Oscar P. B. Wiklander: Karolinska Institutet
Wenyi Zheng: Karolinska Institutet
Rim Jawad Wiklander: Karolinska Institutet
Rui He: Karolinska Institutet.
Doste R. Mamand: Karolinska Institutet
Jeremy Bost: Karolinska Institutet
Guannan Zhou: Karolinska Institutet
Houze Zhou: Karolinska Institutet
Samantha Roudi: Karolinska Institutet
H. Yesid Estupiñán: Karolinska Institutet
Julia Rädler: Karolinska Institutet
Antje M. Zickler: Karolinska Institutet
André Görgens: Karolinska Institutet
Vicky W. Q. Hou: Karolinska Institutet
Radka Slovak: Evox Therapeutics Limited
Daniel W. Hagey: Karolinska Institutet
Olivier G. Jong: Utrecht University
Aileen Geobee Uy: Karolinska Institutet
Yuanyuan Zong: Shandong Provincial Hospital Affiliated to Shandong First Medical University
Imre Mäger: University of Tartu
Carla Martin Perez: Headington
Thomas C. Roberts: Headington
Dave Carter: Evox Therapeutics Limited
Pieter Vader: University Medical Center Utrecht
Elin K. Esbjörner: Chalmers University of Technology
Antonin Fougerolles: Evox Therapeutics Limited
Matthew J. A. Wood: Headington
Roosmarijn E. Vandenbroucke: VIB
Joel Z. Nordin: Karolinska Institutet
Samir EL Andaloussi: Karolinska Institutet

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Intracellular delivery of protein and RNA therapeutics represents a major challenge. Here, we develop highly potent engineered extracellular vesicles (EVs) by incorporating bio-inspired attributes required for effective delivery. These comprise an engineered mini-intein protein with self-cleavage activity for active cargo loading and release, and fusogenic VSV-G protein for endosomal escape. Combining these components allows high efficiency recombination and genome editing in vitro following EV-mediated delivery of Cre recombinase and Cas9/sgRNA RNP cargoes, respectively. In vivo, infusion of a single dose Cre loaded EVs into the lateral ventricle in brain of Cre-LoxP R26-LSL-tdTomato reporter mice results in greater than 40% and 30% recombined cells in hippocampus and cortex respectively. In addition, we demonstrate therapeutic potential of this platform by showing inhibition of LPS-induced systemic inflammation via delivery of a super-repressor of NF-ĸB activity. Our data establish these engineered EVs as a platform for effective delivery of multimodal therapeutic cargoes, including for efficient genome editing.

Date: 2025
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DOI: 10.1038/s41467-025-59377-y

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